Abstract
Deregulation and activation of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian (or mechanistic) target of rapamycin (mTOR) pathway have a major role in proliferation and cell survival in breast cancer. However, as single agents, mTOR inhibitors have had modest antitumor efficacy. In this study, we evaluated the effects of vertical inhibition of mTOR and Akt in breast cancer cell lines and xenografts. We assessed the effects of mTOR inhibitor rapamycin and Akt inhibitor MK-2206, given as single drugs or in combination, on cell signaling, cell proliferation and apoptosis in a panel of cancer cell lines in vitro. The antitumor efficacy was tested in vivo. We demonstrated that MK-2206 inhibited Akt phosphorylation, cell proliferation and apoptosis in a dose-dependent manner in breast cancer cell lines. Rapamycin inhibited S6 phosphorylation and cell proliferation, and resulted in lower levels of apoptosis induction. Furthermore, the combination treatment inhibited phosphorylation of Akt and S6, synergistically inhibited proliferation and induced apoptosis with a higher efficacy. In vivo combination inhibited tumor growth more than either agent alone. Our data suggest that a combination of Akt and mTOR inhibitors have greater antitumor activity in breast cancer cells, which may be a viable approach to treat patients.
Highlights
The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway regulates cell growth, protein translation, autophagy, metabolism and cell survival
Deregulation and activation of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway have a major role in proliferation and cell survival in breast cancer
Activation of PI3K/Akt/mTOR pathway is a central event in many types of cancer and represents a promising target for new treatment strategies
Summary
The phosphoinositide 3-kinase (PI3K)/Akt/mammalian (or mechanistic) target of rapamycin (mTOR) pathway regulates cell growth, protein translation, autophagy, metabolism and cell survival. One or more PI3K pathway components were altered in 38% of cancer patients.[1] Phosphatase and tensin homolog (PTEN) loss (30% by immunohistochemistry), PIK3CA (13%), PTEN (6%) and AKT1 (1%) mutations are common and more frequently observed with hormone receptor overexpression (androgen, progesterone or estrogen receptor) or human epidermal growth factor receptor 2 (HER2) amplification.[1] In vitro data suggest that tumors with a low level PTEN expression or a mutant PIK3CA depend on Akt for oncogenic signaling, such as elevation of phosphorylated Akt levels, is frequently observed in breast cancer and indicate poor prognosis.[2] in breast cancer, PI3K/Akt/mTOR pathway is associated with resistance to endocrine therapy, HER2-directed therapy and cytotoxic therapy.[3,4]
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